1. Biochemistry and Chemical Biology
  2. Computational and Systems Biology
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Mapping the functional versatility and fragility of Ras GTPase signaling circuits through in vitro network reconstitution

  1. Scott Coyle
  2. Wendell A Lim  Is a corresponding author
  1. Howard Hughes Medical Institute, University of California, San Francisco, United States
Research Article
  • Cited 4
  • Views 3,874
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Cite this article as: eLife 2016;5:e12435 doi: 10.7554/eLife.12435

Abstract

The Ras-superfamily GTPases are central controllers of cell proliferation and morphology. Ras signaling is mediated by a system of interacting molecules: upstream enzymes regulate Ras's ability to recruit multiple competing downstream effectors. We developed a dynamic in vitro reconstitution of H-Ras signaling systems. By including upstream regulators and downstream effectors, we mapped how different network configurations shaped the timing and amplitude of outputs. Distortion by oncogenic Ras alleles was dependent on the balance of positive (GEF) and negative (GAP) regulators in the system. Different effectors interpreted the same input with distinct dynamics, enabling a Ras system to encode multiple temporal responses to a single input. Different Ras-to-GEF positive feedback mechanisms reshaped output dynamics in distinct ways, such as amplification or overshoot-minimization. This work provides a design manual for programming these systems to produce an array of dynamic signaling behaviors and reveals numerous paths to altered signaling behaviors associated with disease.

Article and author information

Author details

  1. Scott Coyle

    Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Wendell A Lim

    Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
    For correspondence
    Wendell.Lim@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Philip A Cole, Johns Hopkins University, United States

Publication history

  1. Received: October 20, 2015
  2. Accepted: January 13, 2016
  3. Accepted Manuscript published: January 14, 2016 (version 1)
  4. Version of Record published: February 23, 2016 (version 2)

Copyright

© 2016, Coyle & Lim

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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